Hypoxia-Responsive Aggregation of Iron Oxide Nanoparticles for T₁-to-T₂ Switchable Magnetic Resonance Imaging of Tumors

Magnetic resonance imaging (MRI), one of the most general imaging techniques in the clinic, is widely employed for tumor diagnosis with the assistance of contrast agents (CAs). However, currently available CAs in the clinic suffer from shortcomings of a short blood circulation time, lack of specificity to pathological location, insufficient imaging window, and potential biotoxicity of the gadolinium ion. To overcome these problems, on the basis of extremely small iron oxide nanoparticles (ESIONPs), a hypoxia-responsive T1-to-T2 switchable MRI contrast agent was designed and constructed. In detail, polyacrylic acid-modified ESIONPs (ESIONPs-PAA) were first synthesized, and then, nitroimidazole derivatives and cysteine molecules were sequentially coupled on the surface of ESIONPs-PAA to obtain a hypoxia-responsive MRI contrast agent (HR-ESIONPs). Since 2-nitroimidazole and cysteine molecules on the surface of HR-ESIONPs can form an irreversible bond induced by the nitroreductase in the hypoxic tumor microenvironment, monodispersed HR-ESIONPs could transform into the nanocluster form, which can specially provide T2 contrast enhancement. In vitro experiments show that monodispersed HR-ESIONPs could effectively aggregate in the mimical hypoxic environment of tumors and switch from a T1 to T2 contrast agent. Moreover, in vivo experiments further confirm that HR-ESIONPs could effectively accumulate and realize the MRI signal switch from T1 to T2 contrast enhancement in tumors originating from the aggregation of HR-ESIONPs induced by the hypoxic environment, which promotes the diagnostic precision of tumors. Additionally, with the confirmation of favorable biosafety on cells and mice, hypoxia-responsive HR-ESIONPs are potential platforms to improve the diagnostic accuracy and sensitivity of MRI for tumors.